Anthrax, Smallpox and Multiple Anthrax, Smallpox and Multiple Vaccinations:Vaccinations:

What We Know and Do Not KnowWhat We Know and Do Not Know

Omowunmi (‘Wunmi) Osinubi, MD, M.Sc., MBA, FRCA.

Adjunct Assistant Professor Department of Occupational and Environmental Health

UMDNJ-School of Public Health & Robert Wood Johnson Medical School

Occupational Health PhysicianWar Related Illness and Injury Study Center

Rationale for Military Rationale for Military VaccinationsVaccinations

Vaccines are important for military force health protection in peacetime and in war

Vaccines are administered to protect troops from infectious diseases that are common to US populations

Vaccines are intended to protect troops from serious/deadly diseases in deployment situations and/or from biological warfare agents

Military Service VaccinationsMilitary Service Vaccinations

Routine vaccinations are initiated during basic training Boosters are administered periodically to maintain

immunity for the duration of military service Additional vaccines may be administered in special

circumstances Specific occupational groups as protection against infectious

hazards associated with their job duties (e.g., medical & laboratory personnel)

Overseas deployments with particular endemic infectious diseases (e.g., typhoid, yellow fever e.t.c.)

Suspected biological warfare agents

Vaccines Routinely Vaccines Routinely Administered to All Military Administered to All Military

Recruits (PGW)Recruits (PGW)Vaccine Schedule

Adenovirus 1 oral dose

Influenza Annual shot

Measles 1 shot

Meningococcal 1st shot & booster every 3-5 years

Polio 1 oral dose

Tetanus-Diptheria Booster every 10 years

Rubella I shot

Small pox (through the late 1980s)

1 dose

Vaccines Administered to Special Vaccines Administered to Special Military Occupations (PGW Era)Military Occupations (PGW Era)

Vaccine Personnel Schedule

Plague Marines, Navy, Army, Special forces, at-risk occupations or deployment to at risk areas

 5 shots over 12 monthsthen booster every 1-2 years

 Smallpox  Vaccine or booster to new recruits through the late 1980’s

 1 dose

 Typhoid  Army & Air Force alert forces for deployment to high risk areas

 2 doses in 2 months, then booster every 3 years

 Yellow Fever  Navy, Marines, Army and Air Force alert forces and for deployment to high risk areas

 1st shot, then booster every 10 years

Risk of DyingRisk of Dying

Smoking 10 cigarettes a day One in 200

Road accident One in 8,000

Playing soccer One in 25,000

Homicide One in 100,000

Terrorism attack in 2001 One in 100,000

Hit by lightning One in 10, 000,000

Terrorism attack in 1990’s One in 50,000,000

Anthrax in 2001 One in 50,000,000

Smallpox in 2001 Less than One in 50,000,000

Biological Warfare Threats in Biological Warfare Threats in Persian Gulf ConflictsPersian Gulf Conflicts

Intelligence reports suggested that troops were at risk from weaponized biological warfare agents in Iraq

Biological warfare agents of concern Botulinum toxin Smallpox Anthrax

Biological Weapons (BWs)Biological Weapons (BWs) Biological warfare

Employment in war of biological agents to injure or destroy people, animals, or crops

Dispersal of microbes or their toxins to cause widespread illness, death and terror.

Characteristics of BWs Low visibility High potency Substantial accessibility Relatively easy delivery

History of Biological WarfareHistory of Biological Warfare

Use of BWs date back to antiquity Prior to the 20th Century, there were 3 methods of BW

Deliberate poisoning of food and water Roman literature from 300 BC - animal cadavers were used to

contaminate wells

Biological agents/toxins on weapons system Scythian archers infected their arrows by dipping them into

decomposing bodies or blood mixed with manure – Circa 400BC

Biological agents inoculated on fabrics. During the French & Indian War, British forces in North America

gave blankets from small pox patients to native Americans to create transmission of the disease to immunologically naïve tribes.

History of Biological Warfare History of Biological Warfare Contd.Contd.

In 1900s BW became more sophisticated. During WWI, Germans developed anthrax, glanders, wheat

fungus and cholera as BWs

In 1925, the Geneva protocol signed by 108 nations was the 1st multilateral agreement that extended prohibition of chemical & biological warfare agents. No method for verification of compliance was addressed

WWII and through the 1970’s, Japan, USA, UK had active offensive biological weapons programs

BioterrorismBioterrorism Since 1980’s terrorist organizations have become users of biological

agents

751 persons were infected with Salmonella Typhimurium after intentional contamination of the salad bar in an Oregon restaurant by followers of Bhagwan Shree Rajneesh (1984)

Iraq began an offensive BWs program, producing anthrax, botulinum toxin, and aflatoxin in 1985 After the Persian Gulf War, Iraq disclosed that it had bombs, Scud

missiles, 122-mm rockets, and artillery shells armed with botulinum toxin, anthrax and aflatoxin.

Spray tanks fitted to aircrafts that could distribute 2000 L over a target

The Threat of Bioterrorism The Threat of Bioterrorism Still ExistsStill Exists

"The cold reality is that it is almost impossible to enforce the existing biological weapons treaty.There is no biological weapons facility, which if shut down today could not be rebuilt tomorrow,"

http://news-service.stanford.edu/news/january21/lederberg.html

Biological Warfare Agents Biological Warfare Agents of Concernof Concern

Anthrax Botulinum Toxin Smallpox Plague Ricin Toxin

Encephalitis Virus Tularemia Staph enterotoxin Brucella Ebola/Marbug

AnthraxAnthrax

Acute infectious disease Spore-forming bacterium

Bacillus anthracis Anthrax spores remain viable

in the soil for decades

Commonly occurs in wild and domestic animals including cattle, sheep, goats, camels, antelopes and other herbivores

Incidence of naturally occurring anthrax in the US is approximately one case per year The Anthrax Letters

Clinical Features of AnthraxClinical Features of Anthrax Cutaneous anthrax

Small papule, which progresses to an ulcer with black eschar

More than 95% of cases of anthrax are cutaneous Lesion usually heals in 2-3 weeks Septicemia is rare Mortality rate is 1% if there is adequate treatment

Gastrointestinal anthrax Transmission is from ingestion of infected meat Nausea, vomiting, fever, tonsilar enlargement,

severe abdominal pain, respiratory distress, acute abdomen, massive ascites & diarrhea

Mortality rate 50%

Meningitis

Pulmonary AnthraxPulmonary Anthrax

“Woolsorter’s disease” Fever, malaise, fatigue, myalgia, respiratory distress

which may be followed by onset of shock and death within 24-36 hrs.

Inhalational anthrax is the most likely form of disease to follow military or terrorist attack Such an attack likely will involve aerosolized delivery

of anthrax spores

Mortality rate is 80-90%, but may approach 100% if septic shock.

Of the 11 cases of inhalational anthrax in the 2001 bioterrorism attacks in the US, only 6 patients survived (65% survival rate)

SmallpoxSmallpox

Variola is the most notorious of the poxviruses

Highly infectious by aerosol Environmentally stable Retains infectivity Represents a significant threat as a BW agent

Smallpox is believed by some to have been responsible for the death of more people than any other acute infectious disease.

1980 - WHO declared that endemic small pox had been eradicated. Last known case of smallpox was in Somalia

in 1977

Clinical Features of Clinical Features of SmallpoxSmallpox

Systemic viral disease high fever, headaches,

myalgias, vomiting, abdominal & back pain

skin lesions

Variola major 30% case fatality rate in

unvaccinated persons 3% fatality rate in previously

vaccinated persons.

Botulinum Toxins (BTs)Botulinum Toxins (BTs)

BTs are the most lethal toxin known 10,000 – 100,000 times more toxic

than chemical nerve agents 1 gm crystalline BT can kill > 1 million

people if dispersed and inhaled evenly

0.001 mcg/kg will kill 50% of the exposed population (LD50)

Point source aerosol release Incapacitate/kill 10% of people

downwind within 500 meters (0.3 miles)

Clostridium botulinum

Botulinum Toxin WarfareBotulinum Toxin Warfare

Credible threat as BW agent Extreme potency and lethality Ease of production Ease of transport Need for prolonged intensive care

1991- Iraq weaponized 19,000L of BT during Persian Gulf War

1995 - Iraq admitted to weaponizing and deploying more than 100 munitions with BT

Mechanism of Action of BTMechanism of Action of BT BT binds to the pre-

synaptic terminal of the neuromuscular junction & cholinergic autonomic sites

Prevents release of acetylcholine

Causes muscular weakness & paralysis

Recovery requires months for the neurons to develop new axons

Clinical Features of BotulismClinical Features of Botulism

Classic Triad Symmetric, descending flaccid paralysis with prominent bulbar

palsies Bulbar palsies

Diplopia, dysarthria, dysphonia, dysphagia (four D’s)

Afebrile Clear sensorium – normal mental status exam

Most serious complication of toxicity is respiratory failure With adequate supportive care, mortality rate is <5% Recovery could take months.

BotulismBotulism

Requested to perform max. smile. Ptosis, disconjugate gaze, mild asymmetric smile.

Patient at rest, bilateral mild ptosis, disconjugate gaze, symmetric facial muscles.

JAMA. 2001;285:1059-1070

Risk of DyingRisk of Dying

Smoking 10 cigarettes a day One in 200

Road accident One in 8,000

Playing soccer One in 25,000

Homicide One in 100,000

Terrorism attack in 2001 One in 100,000

Hit by lightning One in 10, 000,000

Terrorism attack in 1990’s One in 50,000,000

Anthrax in 2001 One in 50,000,000

Smallpox in 2001 Less than One in 50,000,000

Mandatory Military Mandatory Military VaccinationsVaccinations

The military first mandated immunizations in 1777 General Washington required troops to receive small pox

vaccines

Since then small pox vaccine has been given to service members during major conflicts Small pox vaccination was suspended in 1990

DOD mandated vaccinations for anthrax and smallpox in 1998 and then in 2002out of concern of BW threats

At time of PGW, new recruits received up to 17 antigens during the first 2 weeks of basic training

Vaccination Adverse EffectsVaccination Adverse Effects No immunization is completely safe

Some service members who received these vaccines have developed severe reactions which they are attributing to vaccines Migraines, heart problems, diabetes multiple sclerosis, medically unexplained neuromuscular and

musculoskeletal problems

Questions have been raised about effects of receiving multiple vaccinations over a short period of time versus reaction to any single vaccine

Case reports of similar health problems in soldiers who received the vaccines but did not actually deploy.

Bio-warfare VaccinesBio-warfare Vaccines

Botulinum Toxoid (BT)Botulinum Toxoid (BT)

Pentavalent BT vaccine was still an investigational vaccine BT was administered to fixed units, forward deployed troops in PGW Schedule was 3 shots over 12 weeks

An estimated 12% of Gulf war vets received BT DOD estimates that 137,850 BT doses were administered in theater 8,000 individuals received at least one dose of BT

Vaccine efficacy trials in the 1960’s Few problems with acute local reactions No problems with severe systemic reactions

CDC monitoring data of 17,000 doses administered prior to 1997 7% had moderate local reaction 0.4% severe reaction Health events were of limited duration

Smallpox VaccineSmallpox Vaccine

Vaccination is safe & effective for most people Mild symptoms

Local soreness & redness Enlarged regional lymph nodes low fever

1 out of 3 people may feel unwell enough to miss work

Serious reactions Vaccinia rash - localized or widespread (generalized vaccinia) Toxic allergic rash to the vaccine (erythema multiforme) 1 in 1000 recipients

Smallpox Vaccine Contd.Smallpox Vaccine Contd.

Life-threatening reactions Eczema vaccinatum

Widespread severe skin infection in persons with eczema or atopic dermatitis

Vaccinia necrosum Extensive tissue destruction leading to death

Post-vaccinal encephalitis

Recent developments Causal association between vaccination & myocarditis Angina & heart attack have been reported post-vaccination Persons with post-vaccination chest pain, shortness of breath or

cardiac disease must seek medical attention ASAP.

Anthrax Vaccine (AVA)Anthrax Vaccine (AVA) AVA was licensed in 1970

Alumnium hydroxide-adsorbed preparation

Vaccination series comprised 6 subcutaneous injections over 18 months 0, 2 & 4 weeks; 6, 12 and 18 months; annual boosters

Studies in rhesus monkeys indicate that AVA is protective of inhalational anthrax Very limited human vaccine efficacy data

AVA Immunization Policies AVA Immunization Policies (PGW)(PGW) There was not enough time or adequate AVA supplies to

vaccinate all the troops in time for deployment

US Central Command (CENTCOM) recommended & designated vaccination process as follows:

2 shots, 2 weeks apart; “low-profile” vaccination process Fixed units & rear deployed troops Personnel in Riyadh, Dharan-Damman areas, King Khalid Military City, Logistic

Bases A, B, C, D, E, Army VII Corps HQ, Army XVII Airborne Corps HQ, Bahrain, 1st Calvary Division

310,680 doses were administered in theater 150,000 troops received one or more shots

41% of all US vets; 30% of Navy Seabees reported receiving AVA

AVA – Public PerceptionAVA – Public Perception Media controversy and public debate fueled by several factors

? Efficacy against inhalational anthrax

? Manufacturing quality control problems

? Short and long-term side effects

? Vaccine components and adjuvants“Squalene” vs Aluminium hydroxide hypotheses

? Military policies that first mandated vaccinations, punished refusals for vaccinations and later retracted mandatory vaccination

? Indications for vaccinations was not uniformly applied

? Vaccinations performed in “secrecy”, inadequate informed consent, and incomplete documentation of anthrax vaccinations

? Variability in vaccines used Differences in vaccines used prior to the 1970s versus Gulf war vaccines Differences in US versus UK military vaccines Differences in reactions/adverse effects associated with different lots of the

AVAs

With Permission -http://www.johnlund.com/page.asp?ID=2154

Short-term Health Effects of AVAShort-term Health Effects of AVA Clinical trials of 1,250 recipients done in the 1950’s

Acute local reaction in 35% Less than 3% of which were severe

CDC unpublished data of 7,000 recipients used for licensure in 1970

(cited by the 2002 IOM report on AVA) Mild reaction in 8%; severe reactions in 0.2% Reanalysis of a subset of data of 1750 recipients

Mild local reactions in 28% of doses Women were 3X more likely than men to have reactions

Post -1998 AVA studies showed much higher rates of local and systemic reactions compared to other vaccines Local reactions 70-80%

Redness, swelling, burning, lump, soreness

Systemic reactions 10-40% Headaches, myalgia, malaise, joint pain, fatigue

Veterans who had acute reactions to deployment-related vaccines, tended to be in poor health years after the war.

Long-term Health Effects of Long-term Health Effects of AVAAVA Earlier studies of AVA provided little information regarding long-term

health effects Individual case reports

Immediate & delayed hypersensitivity reactions, rheumatoid arthritis, optic neuritis, lymphocytic vasculitis, oral pemphigus vulgaris, and demyelinating diseases including multiple sclerosis

Summary of VAERS data for AVA Two studies indicate that AVA had more joint symptoms & GIT problems

reported relative to the other vaccines. The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system

More recent studies - large military health services utilization data Compared rates of hospitalizations, clinic visits, and disability for diagnosed

conditions at 6 weeks to 4 yrs post AVA in troops vs. non-vaccinated troops To date, studies have found few differences in AVA recipients vs. non-

recipients

Gaps in Current KnowledgeGaps in Current Knowledge Current health services utilization research data have

inherent limitations that preclude generalization of research findings Healthy worker effect

Combat ready troops are generally in better fitness and are more likely to have received AVA compared with persons with pre-exisiting disabilities or medical problems

Inclusion of only vets who utilized military health service Excludes persons who left military service – particularly those

medically discharged or felt too unwell to continue service Excludes health conditions that are not severe enough for

hospitalization, but are incapacitating nonetheless

Follow-up periods insufficient to detect health problems that have a long latency period

SummarySummary

Veterans deployed to the Persian Gulf received multiple vaccinations for force protection purposes

AVA is the most controversial of these vaccines There is paucity of empiric research that

provides adequate information about rates of persistent symptoms or multi-symptom illness post anthrax and/or other vaccinations

Considerations for Future Considerations for Future ResearchResearch

Establish a comprehensive database of all Veterans deployed to the Persian Gulf To the extent feasible, obtain deployment exposure history and current health

concerns.

Cohort and/or case-control studies would be helpful to determine whether individual vaccines and/or combinations of vaccines are independent predictors of health problems in Veterans deployed to the Persian Gulf.

Conduct more definitive studies in non-deployed Veterans who received the vaccines versus non-deployed non-recipients, versus deployed vaccine recipients

So Why Should We CareSo Why Should We Careabout Veterans’ Vaccination about Veterans’ Vaccination

concerns?concerns?

So why should we careSo why should we careabout Veterans’ vaccination about Veterans’ vaccination

concerns?concerns?

Because they cared for usBecause they cared for us

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